The Acute Liver Failure Study Group is now in its 7th year of operation, the final year of its current funding. A prospective registry program comprising 24 adult and 24 pediatric sites has collected detailed data, serum, tissue and DNA on more than 750 adults and 300 children with well-defined acute liver failure. Studies by the group have described the overall impact of various disease categories in acute liver failure, in particular that of acetaminophen, the role of viruses and acetaminophen in indeterminate cases, the impact of transplantation and sepsis in determining outcome, and the importance of prognostic factors for survival. The three specific aims of the original study have largely been met or exceeded. More than 30 ancillary studies have been performed using the data and biological materials available;12 original articles have been published. A therapeutic trial of N-acetylcysteine for patients with acute liver failure not due to acetaminophen has exceeded 50% enrollment, with results still blinded at this time. We anticipate finishing the trial in the next 2-3 years with the addition of international sites. The present competing continuation proposal would extend the data, serum, tissue and DNA registry as an available resource for the next 5 years, and take our study of acute liver failure to a new level. Our new aims are to internationalize the study to provide global information from 8-10 sentinel sites on all continents, and to explore in more detailed fashion certain aspects of ALF: psychosocial aspects of acetaminophen toxicity, drug-induced liver injury pathogenesis focused on genetic polymorphisms and intensive care management and liver transplantation. A final aim is to provide the logistical support for new therapy initiatives, even while the MAC study is being completed. Using a wider, global network will provide surveillance against new infectious or toxic agents worldwide, facilitate more detailed studies in certain areas and permit faster accrual of new patients for future therapeutic trials in this rare but frequently fatal condition.